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IDDM in humans and in nonobese diabetic (NOD) mice is a T-cell-dependent autoimmune disease in which the beta-cells of the pancreatic islets are destroyed. Several putative beta-cell autoantigens have been identified, but insulin and its precursor, proinsulin, are the only ones that are beta-cell specific. (Pro)insulin may be a key autoantigen in IDDM. To address the role of proinsulin in the development of IDDM, we generated NOD mice transgenic for the mouse proinsulin II gene driven off a major histocompatibility complex (MHC) class II promoter to direct expression of the transgene to MHC class II bearing cells, including those in the thymus, with the aim of deleting proinsulin-reactive T-cells. The mononuclear cell infiltration of the islets (insulitis) is almost completely absent, and diabetes is prevented in these transgenic NOD mice. The mononuclear cell infiltration of the salivary glands (sialitis) and immune responses to ovalbumin (OVA) are not altered, indicating that the protective effect of the transgene is specific for islet pathology and not due to general immunosuppression. We conclude that autoimmunity to proinsulin plays a pivotal role in the development of IDDM.

The NOD mouse is a model for human insulin-dependent diabetes mellitus. The disease is thought to have an autoimmune etiology because it is T-cell dependent and is characterized by mononuclear cell infiltration in and around the pancreatic islets of Langerhans. The mechanism by which autoreactive T-cells are generated is not fully understood, but it has been postulated that there is a breakdown in self-tolerance induction during intrathymic T-cell maturation. The aim of these studies was to determine whether transplantation of NOD thymus into diabetes-resistant mouse strains would generate islet-reactive T-cells. Neonatal thymus was pretreated either by irradiation or culture in 2-deoxyguanosine (dGua) and then transplanted into athymic BALB/c, CBA, and C57BL/6 nude mice. Generally, insulitis was not seen in the CBA or C57BL/6 recipients, but was found in 56% of BALB/c mice transplanted with an irradiated NOD thymus and in 46% BALB/c mice with a dGua-treated thymus. Similar experiments in which a NOD fetal pancreas was transplanted into nude BALB/c mice before NOD thymus transplantation showed a similar frequency and severity of insulitis in both the host pancreas and grafted NOD pancreas. This suggests that NOD islets are no more prone than the host islets to autoimmune attack and do not exacerbate insulitis. Overall, the data suggest that a defect of thymic origin (and correlating with the thymic epithelium) in the NOD mouse can lead to the development of autoreactive T-cells and specific islet cell damage. Autoreactivity appears to be restricted to the H-2Kd allele that is shared by NOD and BALB/c mice.

Fetal human pancreata, obtained from legally-induced abortions, were placed in organ culture to study their capacity to produce insulin over periods in vitro of between 18 and 40 days. Specimens obtained by hysterotomy usually showed increasing insulin secretion as measured by the insulin content of the media at each twice-weekly medium change. In most instances, relatively little insulin was produced during the first 7-10 days, but thereafter insulin secretion rapidly increased. In contrast, most specimens from prostaglandin-induced abortions showed high levels of insulin in the medium early in the culture period but little thereafter, indicating rapid release of insulin from damaged tissue. In some instances, after early insulin release by damaged tissue, some recovery of islet function occurred and insulin secretion again increased. The presence of differentiated endocrine cells was confirmed histologically. Tissue from each fetus was placed in a number of petri dishes, and for each individual fetus a qualitatively similar pattern of secretion was noted in each dish. These data suggest that representative and nondestructive monitoring of islet function is possible and may be important before such tissue is considered for use in islet transplantation in insulin-dependent diabetes.